WO2015004105A1 - Benzyl-1h-pyrazolo[3,4-b]pyridine und ihre verwendung - Google Patents

Benzyl-1h-pyrazolo[3,4-b]pyridine und ihre verwendung Download PDF

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Publication number
WO2015004105A1
WO2015004105A1 PCT/EP2014/064547 EP2014064547W WO2015004105A1 WO 2015004105 A1 WO2015004105 A1 WO 2015004105A1 EP 2014064547 W EP2014064547 W EP 2014064547W WO 2015004105 A1 WO2015004105 A1 WO 2015004105A1
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WIPO (PCT)
Prior art keywords
methyl
salts
oxides
pyrazolo
solvates
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PCT/EP2014/064547
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German (de)
English (en)
French (fr)
Inventor
Alexandros Vakalopoulos
Alexey Gromov
Markus Follmann
Damian Brockschnieder
Johannes-Peter Stasch
Tobias Marquardt
Adrian Tersteegen
Frank Wunder
Gorden Redlich
Dieter Lang
Volkhart Min-Jian Li
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Bayer Pharma Aktiengesellschaft
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Priority to AU2014289312A priority Critical patent/AU2014289312A1/en
Priority to EP14736803.9A priority patent/EP3019506A1/de
Priority to US14/903,347 priority patent/US9605008B2/en
Priority to AP2016008970A priority patent/AP2016008970A0/xx
Priority to CN201480049852.8A priority patent/CN105745215A/zh
Priority to CA2917682A priority patent/CA2917682A1/en
Priority to MX2016000258A priority patent/MX2016000258A/es
Priority to JP2016524789A priority patent/JP2016523944A/ja
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Priority to KR1020167003065A priority patent/KR20160030541A/ko
Priority to MA38775A priority patent/MA38775A1/fr
Priority to TN2016000006A priority patent/TN2016000006A1/en
Priority to SG11201600038UA priority patent/SG11201600038UA/en
Priority to EA201600096A priority patent/EA201600096A1/ru
Publication of WO2015004105A1 publication Critical patent/WO2015004105A1/de
Priority to PH12016500065A priority patent/PH12016500065A1/en
Priority to IL243525A priority patent/IL243525A0/en
Priority to CUP2016000004A priority patent/CU20160004A7/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine

Definitions

  • the present application relates to novel benzyl-lH-pyrazolo [3,4-b] pyridines, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or Prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • cGMP cyclic guanosine monophosphate
  • NO nitric oxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.
  • CO carbon monoxide
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
  • the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • the dual principle is met for the purposes of the present invention, when the compounds of the invention show an effect on recombinant guanylate cyclase reporter cell lines according to the investigation under B-2 as a minimal effective concentration (MEC) of ⁇ 3 ⁇ and inhibition of human phosphodiesterase 5 (PDE5 ) according to the study under B-3 as IC50 ⁇ 100 tiM.
  • MEC minimal effective concentration
  • PDE5 human phosphodiesterase 5
  • Phosphodiesterase-5 is the name given to one of the enzymes that cleaves the phosphoric acid ester bond in cGMP to give 5'-guanosine monophosphate (5'-GMP).
  • phosphodiesterase-5 occurs predominantly in the smooth muscle of the penile erectile tissue (corpus cavernosum penis) and the pulmonary arteries.
  • Blocking of cGMP degradation by inhibition of PDE5 leads to increased signals of the relaxation signaling pathways and in particular to increased blood supply to the penile erectile tissue and pressure reduction in the blood vessels of the lung. They are used to treat erectile dysfunction and pulmonary arterial hypertension.
  • WO 2004/009590 describes Pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS diseases.
  • WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines as sGC activators.
  • the sGC stimulators described in WO 2012/004259 are fused aminopyrimidines and in WO 2012/004258, WO 2012/143510 and WO 2012/152629 fused pyrimidines and triazines.
  • WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for the treatment of cardiovascular diseases.
  • the object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase and as stimulators of soluble guanylate cyclase and phosphodiesterase-5 inhibitors (dual principle) and have a similar or improved therapeutic profile compared to the compounds known from the prior art , such as for their in vivo properties, such as their pharmacokinetic and pharmacodynamic behavior and / or their metabolism profile and / or their dose-response relationship.
  • the present invention relates to compounds of the general formula (I)
  • R is hydrogen or fluorine
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen, chlorine or fluorine, is hydrogen, chlorine, fluorine or methyl, with the proviso that at least two of the radicals R 1 , R 2 , R 3 or R 4 are different from hydrogen,
  • R 5 is hydrogen or fluorine
  • R 6 is methyl
  • R 7 is methyl
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammoni
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts in which is hydrogen or fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • the compound having the systematic name 3 - [1- (2,4-difluorobenzyl) -5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl is preferred ] -7,7-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-e] [l, 2,4] triazine-6-one and the structural formula (IE)
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • the compound with the systematic name 3 - [1 - (2,6-difluorobenzyl) -5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl is preferred ] -7,7-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-e] [l, 2,4] triazine-6-one and the structural formula (IM)
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • the compound with the systematic name 3 - [5-fluoro-1- (3-fluoro-4-methylbenzyl) -6-methyl-1H-pyrazolo [3,4-b] pyridine-3 is preferred -yl] -7,7-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-e] [l, 2,4] triazine-6-one and the structural formula (IO)
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • N-oxides as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Preferred in the context of the present invention is the compound having the systematic name 3 '- [1- (2-fluoro-4-methylbenzyl) -6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl] spiro [cyclopropane-l, 7'-pyrrolo [2,3-e] [l, 2,4] triazine] -6 '(5'H) -one and the structural formula (IV)
  • the compounds of the present invention act as potent stimulators of soluble guanylate cyclase and inhibitors of phosphodiesterase-5, have valuable pharmacological properties, and have an improved therapeutic profile, such as in vivo properties and / or their pharmacokinetic and / or metabolic profile. They are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase.
  • the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, for example, EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
  • the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and the ventricles as well as conduction disorders such as atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles , AV junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aor
  • cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital Heart failure, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, cardiomyopathy of alcoholic toxicity, cardiac Storage disorders, diastolic heart failure and sy
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome.
  • the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis
  • the compounds according to the invention are also suitable for the treatment of muscular dystrophy, such as the muscular dystrophy Becker-Kiener (BMD) and Duchenne muscular dystrophy (DMD).
  • the compounds according to the invention are suitable for the treatment of urological diseases such as, for example, benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), Benign Prostate Enlargement (BPE), Bladder Discharge Disorder (BOO), Lower Urinary Syndromes (LUTS, including Feiines Urological Syndrome (FUS)), Urogenital System Disorders including Neurogenic Overactive Bladder (OAB) and (IC), Incontinence (UI ) such as mixed, urgency, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostate syndrome
  • BPH benign prostatic hyperplasia
  • BPE Benign Prostate Enlargement
  • BOO Bladder Discharge Disorder
  • LUTS Lower Urinary Syndromes
  • LUTS including Feiines Urological Syndrome (FUS)
  • Urogenital System Disorders including Neurogenic Overactive Bladder (OAB) and (IC)
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hyperten
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF cyst
  • the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
  • they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also
  • the compounds according to the invention are also suitable for regulating cerebral perfusion and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds according to the invention can be used to combat pain and tinnitus.
  • cerebral infarct events Apoplexia cerebri
  • cerebral infarct events such as stroke, cerebral ischaemias and craniocerebral trauma
  • the compounds according to the invention can be used to combat pain and tinnitus.
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis atitis
  • Peritonitis rheumatoid diseases
  • inflammatory skin diseases as well as inflammatory eye diseases.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
  • the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics; and / or lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors as exemplified and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
  • Antithrombotic agents are preferably understood as meaning compounds from the
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and Eplerenone and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide administered.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium sparing diuretics such as amiloride and triamterene
  • aldosterone antagonists such as spironolactone, potassium canrenoate and Eplerenone and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide administered.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccines (CETi-1).
  • a CETP inhibitor such as, by way of example and by way of preference, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccines (CETi-1).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • T3 3,5,3'-triiodothyronine
  • CGS 23425 CGS 23425
  • axitirome CGS 26214
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastat
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention quickly and / or modified donating application forms, the Compounds according to the invention in crystalline and / or amorphised and / or dissolved form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • compositions according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • adjuvants include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers For example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example, antioxidants such as
  • the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg / kg of body weight.
  • Instrument MS Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.0x50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A -> 0.2 min 98% A -> 3.0 min 5% A ⁇ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.
  • Method 6 Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 ⁇ 50 x 3 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 100% A -> 2.75 min 5% A -> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.
  • Method 7 (LC-MS):
  • Instrument Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 mx 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Inlet: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).
  • Variant A A mixture of 2.47 g (6.13 mmol) of 1- (2,3-difluorobenzyl) -5-fluoro-3-iodo-6-methyl-1H-pyrazolo [3,4-b] pyridine from Example 3A and 0.576 g (6.43 mmol) of copper (I) cyanide was dissolved in 12.1 ml abs. DMSO presented in a heated flask and stirred at 150 ° C for 3 h. The cooled reaction solution was added with ethyl acetate and washed three times with a mixture of half-saturated ammonium chloride solution and concentrated ammonia solution (3/1). The organic phase was dried over sodium sulfate, filtered and evaporated.
  • the crude product was purified by flash chromatography (eluent: cyclohexane / ethyl acetate gradient: 15/1 to 10/1, then dichloromethane / methanol: 10/1). 780 mg of the target compound (42% of theory) were obtained.
  • Variant B 650 mg (1.56 mmol, purity 77%) of 1- (2,3-difluorobenzyl) -5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide of the Example 5A
  • the compound obtained was initially charged in 2.7 ml of THF and admixed with 0.49 ml (6.0 mmol) of pyridine. Thereafter, 0.85 ml (6.0 mmol) of trifluoroacetic anhydride were slowly added dropwise with stirring, followed by stirring at RT for 3 h. The reaction solution was added with water and extracted three times with ethyl acetate.
  • the target compound was formed as a minor component in the preparation of the starting compound 4A. After flash chromatography, 650 mg (26% of theory, purity 77%) of the target compound were obtained.
  • Example 7A (2,3-Difluorobenzyl) -5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridine-3-carboximidohydrazide
  • the filtrate was washed with 940 ml of a 25% aqueous ammonia solution, 830 ml of half-concentrated aqueous ammonium chloride solution and 410 ml of saturated sodium chloride aqueous solution.
  • the organic phase was dried over sodium sulfate, filtered and then concentrated in vacuo.
  • the crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate: 3/1, then with dichloromethane / methanol gradient). 7.50 g (85% of theory) of the target compound were obtained.
  • the filter residue was washed with ethyl acetate.
  • the organic phase was separated and washed three times with a mixture of saturated aqueous ammonium chloride solution and concentrated aqueous ammonia solution (3/1) until the aqueous phase was colorless.
  • the organic phase was washed once with saturated aqueous sodium chloride solution, then dried over sodium sulfate, concentrated and dried overnight under high vacuum.
  • the title compound 0.74 g (76% of theory, purity 76%) was used without further purification in the next step.
  • the mixture was then extracted three times with ethyl acetate.
  • the combined organic phases were concentrated, the residue treated with 800 ml of diethyl ether, washed three times with water (200 ml, 400 ml, 200 ml) and once with aqueous sodium chloride solution, concentrated and dried under high vacuum.
  • the residue was added with dichloromethane and filtered.
  • the filtrate was applied to a silica gel column and purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate gradient). There were obtained 4.05 g of the target compound (36% of theory, purity 88%).
  • the reaction mixture was stirred for 10 min at -78 ° C and then warmed to RT over 2 h. It was diluted with 700 ml of methyl tert-buty lether, the precipitate was filtered off and the filtrate was concentrated at 30 ° C and 100 mbar. The residue was purified by flash chromatography (eluent: dichloromethane). This gave 7.30 g (97% of theory, purity about 95%> by NMR) of the title compound.
  • the temperature of the reaction mixture in the flask was always kept below -10 ° C. After completion of the addition, the reaction mixture was saturated at -20 ° C with hydrogen chloride (about 10 min), the cooling bath was removed and then stirred for 1 h at RT. The reaction mixture was concentrated at RT (to 7-8 mbar), the residue (12.4 g of solid) at 0 ° C with 28 ml of ice water, stirred for 30 min at 0 ° C and then at RT overnight. The reaction mixture was mixed with 70 ml of ethyl acetate, stirred for 5 min at RT and then the phases were separated. The aqueous phase was extracted three times with ethyl acetate.
  • Example 20A Equivalent) from Example 20A suspended in a mixture of acetic acid / ethanol (1 / 4.6 volume ratio, 20 equivalents of acetic acid, about 0.2 molar concentration of 5-fluoro-1- (4-methoxybenzyl) -6-methyl-1H-pyrazolo [3, 4-b] pyridine-3-carboximidohydrazide), added in portions.
  • the reaction mixture is stirred for 1 h under reflux. After cooling, the reaction mixture is concentrated on a rotary evaporator. The residue is purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with the addition of 0.05% formic acid or 0.1% TFA).
  • reaction solution of ethyl 1- ⁇ 5-chloro-3- [5-fluoro-1- (4-methoxybenzyl) -6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl] -1, 2,4-triazin-6-yl ⁇ cyclopropanecarboxylate from Example 38A is diluted with dry acetonitrile (about 0.01-0.05 molar concentration) and then slowly added to a cooled to 0 ° C 33% aqueous ammonia solution (72 ml of this ammonia solution per 1 mmol of ethyl 1 - ⁇ 5-chloro-3 - [5-fluoro-1 - (4-methoxybenzyl) -6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl] -1 , 2,4-triazin-6-yl ⁇ cyclopropanecarboxylate) is added dropwise while keeping the internal temperature between 0-12
  • the reaction mixture is concentrated on a rotary evaporator.
  • the residue is mixed with water and extracted three times with dichloromethane.
  • the combined organic phases are washed twice with water and once with saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated in vacuo.
  • the crude product is purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.05% formic acid or 0.1% TFA).
  • the product fractions obtained are taken up in dichloromethane and twice washed with saturated aqueous sodium bicarbonate solution.
  • the combined organic phases are dried over sodium sulfate, filtered and concentrated.
  • the residue was concentrated twice from dioxane and once from toluene in vacuo at 30 ° C and then dried under high vacuum. It was mixed with 5 ml of THF and 5 ml of 5% aqueous ammonia solution and left for 5 min at RT. The Jrsgmisch was concentrated in vacuo at 30 ° C, and the residue was concentrated twice from a mixture of 5 ml of THF and 5 ml of 5% aqueous ammonia solution in vacuo at 30 ° C. The residue was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with the addition of 0.05% of> formic acid). 40 mg (46% of theory, purity about 90%> by NMR) of the title compound were obtained.
  • the crude product was abs. 9.6 ml. Dioxane and 2.4 ml of acetic acid and stirred for 8 h at 100 ° C in the microwave. The mixture was concentrated and the residue was stirred with water for 30 min. The solid contained was filtered off and dried under high vacuum. The solid was admixed with 5.5 ml of ethanol. The suspension was heated to 50 ° C and treated with 3.3 ml of dichloromethane, so that a clear solution was formed. After cooling to 0 ° C., a first product fraction of the target compound was filtered off as a solid (241 mg). The filtrate was evaporated and treated with 3 ml of ethanol.
  • the mixture was treated for 1.5 h in an ultrasonic bath.
  • the solid was filtered off, washed with water and a little acetonitrile and dried under high vacuum.
  • the residue was dissolved in DMF (a few drops) and dichloromethane and purified by flash chromatography (eluent: cyclohexane / ethyl acetate gradient).
  • the product fractions were concentrated and the residue was added with ethyl acetate and diisopropyl ether.
  • the solid was filtered off with suction and dried under high vacuum.
  • Example 40A 5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl) spiro [cyclopropane-l, 7'-pyrrolo [2,3-e] [l, 2, 4] triazine] -6 '(5'H) -one (1 equivalent) from Example 40A is initially charged in DMF (about 0.1 molar concentration) and heated to 80 ° C. Cesium carbonate (4 equivalents) is added to the mixture and stirred for 10 minutes.
  • the crude product is dissolved in methylene chloride / methanol / 1N solution of ammonia in methanol (2/2/1) and purified by thick layer chromatography (eluent: dichloromethane / methanol) or alternatively by preparative HPLC (RP-C18, eluent: acetonitrile / water). Gradient with the addition of 0.1% TFA).
  • Example 40A 5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl) spiro [cyclopropane-l, 7'-pyrrolo [2,3-e] [l, 2, 4] triazine] -6 '(5'H) -one (1 equivalent) from Example 40A is initially charged in DMF (about 0.1 molar concentration) and heated to 80 ° C. Cesium carbonate (4 equivalents) is added to the mixture followed by stirring for 10 minutes.
  • the crude product is dissolved in methylene chloride / methanol / 1N solution of ammonia in methanol (2/2/1) and purified by thick layer chromatography (eluent: dichloromethane / methanol) or alternatively by preparative HPLC (RP-C18, eluent: acetonitrile / water). Gradient with the addition of 0.1% TFA).
  • Example 40A 5-fluoro-6-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl) spiro [cyclopropane-l, 7'-pyrrolo [2,3-e] [l, 2, 4] triazine] -6 '(5'H) -one (1 equivalent) from Example 40A is initially charged in DMF (about 0.1 molar concentration) and heated to 80 ° C. Cesium carbonate (4 equivalents) is added to the mixture and stirred for 10 minutes.
  • the crude product is dissolved in methylene chloride / methanol / 1N solution of ammonia in methanol (2/2/1) and purified by thick layer chromatography (eluent: dichloromethane / methanol) or alternatively by preparative HPLC (RP-C18, eluent: acetonitrile / water). Gradient with the addition of 0.1% TFA).
  • the aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10.
  • the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on a chart recorder.
  • phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC 5 o value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
  • the cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).
  • PDE 5 preparations are prepared from human platelets by digestion (Microfluidizer®, 800 bar, 3 passages), followed by centrifugation (75,000 g, 60 min, 4 ° C) and ion exchange chromatography of the supernatant on a Mono Q 10/10 column ( linear sodium chloride gradient, elution with a 0.2-0.3 M solution of sodium chloride in buffer (20 mM Hepes pH 7.2, 2 mM magnesium chloride), fractions having PDE 5 activity are pooled (PDE 5 preparation) and at -80 ° C stored.
  • test substances are resolved to determine their in vitro effect on human PDE 5 in 100% DMSO and serially diluted.
  • Dilution series (1: 3) are typically prepared from 200 ⁇ to 0.091 ⁇ (resulting final concentrations in the assay: 4 ⁇ to 0.0018 ⁇ ). 2 ⁇ l each of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate-96 / 200W, Perkin Elmer). Subsequently, 50 ⁇ of a dilution of the above-described PDE 5 preparation is added.
  • the dilution of the PDE 5 preparation is chosen such that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1: 100; dilution buffer: 50 mM Tris / hydrochloric acid pH 7.5, 8.3 mM Magnesium chloride, 1.7mM EDTA, 0.2% BSA).
  • the substrate [8- ⁇ ] cyclic guanosine 3 ', 5'-monophosphate (1 ⁇ / ⁇ , Perkin Elmer) is 1: 2000 with assay buffer (50 mM Tris / hydrochloric acid pH 7.5, 8.3 mM magnesium chloride, 1.7 mM EDTA) on a concentration of 0.0005 ⁇ / ⁇ diluted.
  • the enzyme reaction is finally started.
  • the test mixtures are incubated for 60 min at room temperature and the reaction is stopped by adding 25 ⁇ l of a suspension of 18 mg / ml Yttrium Scintillation Proximity Beads in water (phosphodiesterase beads for SPA assays, RPNQ 0150, Perkin Elmer).
  • the microtiter plates are sealed with a foil and left for 60 min at room temperature. The plates are then measured for 30 s per well in a Microbeta scintillation counter (Perkin Elmer).
  • IC 50 values are determined on the basis of the plot of the substance concentration versus the percentage PDE 5 inhibition.
  • a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components:
  • Physiotel® receivers connected to a data acquisition computer via a multiplexer (DSI Data Exchange Matrix).
  • the telemetry system allows continuous recording of blood pressure, heart rate and body movement on awake animals in their habitual habitat.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the Telemetry Transmitter TAH PA - C40 is surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The way instrumented animals are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobarbital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobarbital Nembutal, Sanofi: 50 mg / kg i.p.
  • the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD TM, 3M).
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • a solvent-treated group of animals is used as a control.
  • the existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
  • the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
  • the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
  • SBP Systolic blood pressure
  • DBP Diastolic blood pressure
  • ACT Activity - Activity
  • the measured value acquisition is repeated computer-controlled in 5-minute intervals.
  • the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI). Unless otherwise stated, the administration of the test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS).
  • the blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
  • organ-protective effects of the compounds according to the invention are shown in a therapeutically relevant "low nitric oxide (NO) / high renin" hypertension model in rats
  • NO nitric oxide
  • the study was carried out on the basis of the recently published publication (Sharkovska Y, et al., J Hypertension 2010; 28: 1666-1675), where renin transgenic rats (TGR (mRen2) 27) administered the NO synthase inhibitor L-NAME via the drinking water are treated simultaneously with the compound or vehicle according to the invention for several weeks
  • TGR renin transgenic rats
  • L-NAME renin transgenic rats
  • a telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, is used for the blood pressure measurement on conscious dogs described below.
  • the system consists of implantable pressure transmitters, receivers and a data acquisition computer.
  • the telemetry system allows continuous recording of blood pressure and heart rate on awake animals.
  • the telemetry transmitters used are surgically implanted in the experimental animals under aseptic conditions prior to the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the examinations are performed on adult male beagle dogs. Technical details can be found in the documentation of the manufacturer (DSI).
  • a vehicle-treated group of animals is used as a control.
  • hypoxia For measurements under hypoxia conditions, the animals are transferred to a chamber in which there is a hypoxic atmosphere (about 10% oxygen content). This is produced by commercially available hypoxic generators (Hoehenbalance, Cologne, Germany). in the For example, one hour and five hours after substance administration, the dogs are transferred to the hypoxia chamber for 30 minutes.
  • the measurement of pressure and heart rate by telemetry takes place about 10 minutes before and after entering the hypoxia chamber, as well as during the stay in the hypoxia chamber. evaluation
  • hypoxia causes a rapid increase in PAP in healthy dogs. By adding substances, this increase can be reduced.
  • the data smoothed by averaging are compared before and during the hypoxia period.
  • the graphical representation of the curves of the measured parameters is done with the Prism software (GraphPad, USA).
  • the pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats, female beagle dogs and female cynomolgus monkeys.
  • Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation and in dogs and monkeys using a water / PEG400 / ethanol formulation.
  • Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation. Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration.
  • the operation is carried out at least one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.).
  • an analgesic atropine / rimadyl (3/1) 0.1 mL s.c.
  • the blood collection (usually more than 10 times) takes place in a time window, which includes terminal times of at least 24 to a maximum of 72 hours after substance administration.
  • the blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.
  • the pharmacokinetic parameters such as AUC, C max , F (bioavailability), tm (terminal half-life), MRI (Mean Residence Time) and CL (clearance) are calculated from the plasma concentration-time profiles determined using a validated pharmacokinetic calculation program. Since the substance quantification is carried out in plasma, the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. The plasma is recovered by centrifugation at 1000 g. After measuring the concentrations in plasma and blood (by means of LC-MS (/ MS), see above ), the CBiut / Cpi aS ma value is determined by quotient formation.
  • CYP cytochrome P450
  • the compounds of the invention were incubated at a concentration of about 0.1-10 ⁇ .
  • stock solutions of the compounds according to the invention with a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1: 100 dilution into the incubation mixture.
  • the liver microsomes and recombinant enzymes were incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C.
  • Primary hepatocytes were also incubated in suspension in Williams E medium also at 37 ° C.
  • the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15,000 ⁇ g. The samples thus stopped were either analyzed directly or stored at -20 ° C until analysis.
  • the analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS).
  • HPLC-UV-MS / MS high performance liquid chromatography with ultraviolet and mass spectrometric detection
  • the supernatants of the incubation samples are chromatographed with suitable C18-reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid.
  • the UV chromatograms in combination with mass spectrometry data are used to identify, structure elucidate and quantitate the metabolites, and the quantitative metabolic decrease of the compound according to the invention in incubation batches.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv -Solution:
  • the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution).
  • a physiologically acceptable solvent e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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KR1020167003065A KR20160030541A (ko) 2013-07-10 2014-07-08 벤질-1H-피라졸로[3,4-b]피리딘 및 그의 용도
EP14736803.9A EP3019506A1 (de) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridine und ihre verwendung
MA38775A MA38775A1 (fr) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridine et utilisation de cette dernière
CN201480049852.8A CN105745215A (zh) 2013-07-10 2014-07-08 苯甲基-1H-吡唑并[3,4-b]吡啶及其用途
CA2917682A CA2917682A1 (en) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
MX2016000258A MX2016000258A (es) 2013-07-10 2014-07-08 Bencil-1h-pirazolo[3,4-b]piridinas y su uso.
JP2016524789A JP2016523944A (ja) 2013-07-10 2014-07-08 ベンジル−１Ｈ−ピラゾロ［３，４−ｂ］ピリジンおよびその使用
AU2014289312A AU2014289312A1 (en) 2013-07-10 2014-07-08 Benzyl-1H-pyrazolo(3,4-b)pyridines and use thereof
US14/903,347 US9605008B2 (en) 2013-07-10 2014-07-08 Benzyl-1H-pyrazolo[3,4-b]pyridines and use thereof
AP2016008970A AP2016008970A0 (en) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
TN2016000006A TN2016000006A1 (en) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
SG11201600038UA SG11201600038UA (en) 2013-07-10 2014-07-08 Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
EA201600096A EA201600096A1 (ru) 2013-07-10 2014-07-08 Бензил-1н-пиразол[3,4-b]пиридины и их применение
PH12016500065A PH12016500065A1 (en) 2013-07-10 2016-01-08 Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
IL243525A IL243525A0 (en) 2013-07-10 2016-01-10 Benzyl-1h-pyrazolo[4,3-b]pyridines and their use
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